This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of sulfamato hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors.
Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).
The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
Metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-xcex1, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal, and TNF can help control the growth of tumor cells.
TNF-xcex1 convertase is a metalloprotease involved in the formation of soluble TNF-xcex1. Inhibition of TNF-xcex1 convertase (TACE) inhibits production of active TNF-xcex1. Compounds that inhibit both MMPs activity and TNF-xcex1 production have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376 558-561 (1994)). There remains a need for effective MMP inhibitors. There also remains a need for effective TNF-xcex1 convertase inhibiting agents.
MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-Amyloid Precursor Protein) to the amyloid plaque and inactivation of xcex11-protease inhibitor (xcex11-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as xcex11-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase A or B, or collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMPs), xcex12-macroglobulin and their analogs or derivatives. These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997). In addition, application EP 0757 984 A1 discloses aromatic sulfonamide hydroxamates in which the sulfonamido sulfonyl group is bonded on 1 side to a phenyl ring and the sulfonamido nitrogen is bonded to the hydroxamate group via a chain of 1 to four carbon atoms.
One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
International application WO 98/38163, published on Sep. 3, 1998 disclose a large group of hydroxamate inhibitors of MMPs and TACE. The compounds of WO 98/38163 contain 1 or 2 substituents adjacent to the hydroxamate functionality and a substituent that can be an aromatic sulfonyl group adjacent to those 1 or 2 substituents.
International application WO 98/37877, published on Sep. 3, 1998 discloses compounds that contain a 5- to 7-membered heterocyclic ring adjacent to the hydroxamate functionality and can contain an aromatic sulfonyl group adjacent to the heterocyclic ring.
More recently, WO 99/24399, published on May 20, 1999, teaches hydroxamate compounds said to have activity in inhibiting MMP and TNF. Those inhibitors are exemplified by compounds having a 3 carbon atom chain linked to a sulfonamido group. The hydroxamate carbon is linked to a carbon that can be substituted and that carbon is linked to a methylene. The methylene is linked to a sulfonyl that is bonded to a nitrogen that is further substituted. This disclosure also lacks disclosure as to possible specificity of activity among the substrate enzymes.
Another recent disclosure is that of WO 99/29667, published on Jun. 17, 1999, that discloses 1 carbon hydroxamate containing a sulfonamido group whose nitrogen atom is in a ring that is typically bonded directly to another 1 or 2 ring group without the intermediacy of another atom. This publication suggests that some of its compounds are selective inhibitors, but provides scant data for only seven compounds.
Although many of the known MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPs, those compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use. In addition, it can be therapeutically advantageous to utilize a medicament that is selective in its activity as compared to a generally active material so that treatment can be more closely tailored to the pathological condition presented by the host mammal. The disclosure that follows describes a process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits 1 or more MMPs, while exhibiting less activity against at least MMP-1.
The present invention is directed to a treatment process that comprises administering a contemplated sulfamato hydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. A contemplated molecule, inter alia, exhibits excellent inhibitory activity of 1 or more matrix metalloprotease (MMP) enzymes, such as MMP-2 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1. By xe2x80x9csubstantially lessxe2x80x9d it is meant that a contemplated compound exhibits an IC50 value ratio against 1 or both of MMP-2 or MMP-13 as compared to its IC50 value against MMP-1, e.g., IC50 MMP-2:IC50 MMP-1, that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay utilized hereinafter. The invention also contemplates particular compounds that selectively inhibit the activity of MMP-2 to a greater extent than MMP-13, as well as a composition containing such a MMP inhibitor as active ingredient and a process for using the same. A contemplated compound also exhibits inhibition of the activity of the adamalysin family of enzymes, exemplified by the enzyme ADAM 10. The invention further contemplates intermediates in the preparation of a contemplated sulfamato hydroxamic acid molecule and a process for preparing a sulfamato hydroxamic acid molecule.
Briefly, one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated sulfamato hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease and adamalysin activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. The administered enzyme inhibitor sulfamato hydroxamic acid (hydroxamate) corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof: 
Here, R1 and R2 are preferably taken together with the carbon to which they are bonded form a cycloalkyl or more preferably a heterocyclo group either of which is optionally substituted by 1, 2, or 3 Rx substituents, or R1 and R2 are independently selected from the group consisting of:
hydrido,
an alkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkynyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an aryl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an aryloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkyl or bicycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkylalkyl or bicycloalkylalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkyloxyalkyl or bicycloalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkylalkyloxyalkyl or bicycloalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkylthioalkyl or bicycloalkylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx,
cycloalkylalkylthioalkyl or bicycloalkylalkylthioalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a heterocyclo group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a heterocycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents
a heteroaryl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a biarylalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkynyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a heterocycloalkylthio group, optionally substituted with 1, 2, or 3 substituents selected independently from Rx substituents,
a heterocycloalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents selected independently from Rx substituents,
a heteroarylalkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents, and
a heteroarylalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents.
Rx is selelected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, RcRd-amino (xe2x80x94NRcRd), RcRd-aminoalkyl, nitro, nitroso, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, alkoxyalkyl, Rc-oxyalkyl, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, alkyloxycarbonyl-Rc-amino, arylalkyloxycarbonyl-Rc-amino, aryloxycarbonyloxy, carboxy, RcRd-aminocarbonyloxy, RcRd-aminocarbonyl, RcRd-aminoalkanoyl, hydroxy-Rc-aminocarbonyl, RcRd-aminosulfonyl, arylsulfonyl(Rc)amino, RcRd-aminoalkoxy, RcRd-aminocarbonyl(Rc)amino, trifluoromethylsulfonyl(Rc)amino, heteroarylsulfonyl-(Rc)amino, alkylsulfonyl, arylsulfonyl(Rc)amino, arylsulfonyl(Rc)aminocarbonyl, alkylsulfonyl-(Rc)amino, arylcarbonyl(Rc)-aminosulfonyl, and alkylsulfonyl(Rc)aminocarbonyl. Rc and Rd are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with 1 or 2 Ry radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with 1, 2, or 3 substituents independently selected from Rw substituents or a heteroaryl group optionally substituted with 1, 2, or 3 substituents independently selected from Rv substituents. Ry is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and hydroxyalkyl, each of which groups is optionally substituted by 1 or 2 substituents independently selected from Ru substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups.
Rv is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RyRz-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RyRz-aminocarbonyloxy, RyRz-aminocarbonyl, RyRz-aminoalkanoyl, hydroxyaminocarbonyl, RyRz-aminosulfonyl, RyRz-aminocarbonylay)amino, trifluoromethylsulfonyl(Ry)amino, heteroarylsulfonyl-(Ry)amino, arylsulfonyl(Ry)amino, arylsulfonyl(Ry)-aminocarbonyl, alkylsulfonyl(Ry)amino, arylcarbonyl-(Ry)aminosulfonyl, and alkylsulfonyl(Ry)-aminocarbonyl.
Rw is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RyRz-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RyRz-aminocarbonyloxy, RyRz-aminocarbonyl, RyRz-aminoalkanoyl, hydroxyaminocarbonyl, RyRz-aminosulfonyl, RyRz-aminocarbonyl(Ry)amino, trifluoromethylsulfonyl(Ry)amino, heteroarylsulfonyl-(Ry)amino, arylsulfonyl(Ry)amino, arylsulfonyl(Ry)-aminocarbonyl, alkylsulfonyl(Ry)amino, arylcarbonyl-(Ry)aminosulfonyl, and alkylsulfonyl(Ry)-aminocarbonyl.
Rz is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and hydroxyalkyl, each of which groups are optionally substituted by 1 or 2 Ru substituents.
Ru is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and alkyloxycarbonyl.
As to R3a and R3b:
R3a and R3b are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, aryl, heterocyclo, heteroaryl, cycloalkyl, and an alkoxyalkyl group, each of which groups is optionally substituted by an xe2x80x94AREY substituent, wherein:
A is:
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94Sxe2x80x94,
(3) xe2x80x94N(Re)xe2x80x94,
(4) xe2x80x94COxe2x80x94N(Re) or xe2x80x94N(Re)xe2x80x94COxe2x80x94,
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94,
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94,
(7) xe2x80x94HCxe2x95x90CHxe2x80x94,
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94,
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94,
(10) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94,
(11) xe2x80x94Nxe2x95x90Nxe2x80x94,
(12) xe2x80x94NHxe2x80x94NHxe2x80x94,
(13) xe2x80x94CSxe2x80x94N(Re)xe2x80x94 or xe2x80x94N(Re)xe2x80x94CSxe2x80x94,
(14) xe2x80x94CH2xe2x80x94,
(15) xe2x80x94Oxe2x80x94[(CH2)1-8]xe2x80x94 or xe2x80x94[(CH2)1-8]Oxe2x80x94,
(16) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94, or
(17) absent and R is directly connected to R3a or R3b, or both R3a and R3b;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with 1 or 2 radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
E is:
(1) xe2x80x94CO(Rw)xe2x80x94 or xe2x80x94(Rw)COxe2x80x94,
(2) xe2x80x94CON(Re)xe2x80x94 or xe2x80x94(Re)NCOxe2x80x94,
(3) xe2x80x94COxe2x80x94,
(4) xe2x80x94SO2xe2x80x94Rw or xe2x80x94RwSO2xe2x80x94,
(5) xe2x80x94SO2xe2x80x94,
(6) xe2x80x94N(Re)xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94N(Re)xe2x80x94, or
(7) absent and R is bonded directly to Y; and
Y is absent or selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Rcoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein the aryl, heteroaryl, or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and amino, wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 substituents independently selected from hydrido, alkyl, and aralkyl; and
Re is selected from hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl, and Rc, Rd and Rw are as defined before; or
R3a and R3b taken together with the nitrogen atom to which they are bonded form xe2x80x94GAREY, wherein:
G is N-heterocyclo;
A is:
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94Sxe2x80x94,
(3) xe2x80x94NRexe2x80x94,
(4) xe2x80x94COxe2x80x94N(Re) or xe2x80x94N(Re)xe2x80x94COxe2x80x94,
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94,
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94,
(7) xe2x80x94HCxe2x95x90CHxe2x80x94,
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94,
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94,
(10) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94,
(11) xe2x80x94Nxe2x95x90Nxe2x80x94,
(12) xe2x80x94NHxe2x80x94NHxe2x80x94,
(13) xe2x80x94CSxe2x80x94N(Re)xe2x80x94 or xe2x80x94N(Re)xe2x80x94CSxe2x80x94,
(14) xe2x80x94CH2xe2x80x94,
(15) xe2x80x94Oxe2x80x94[(CH2)1-8]xe2x80x94 or xe2x80x94[(CH2)1-8]Oxe2x80x94,
(16) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94, or
(17) absent and R is directly connected to G;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with 1 or 2 radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
E is:
(1) xe2x80x94CO(Rw)xe2x80x94 or xe2x80x94(Rw)COxe2x80x94,
(2) xe2x80x94CONHxe2x80x94 or xe2x80x94HNCOxe2x80x94,
(3) xe2x80x94COxe2x80x94,
(4) xe2x80x94SO2xe2x80x94Rwxe2x80x94 or xe2x80x94Rwxe2x80x94SO2xe2x80x94,
(5) xe2x80x94SO2xe2x80x94,
(6) xe2x80x94NHxe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94NHxe2x80x94, or
(7) absent and Y is bonded directly to R; and
Y is absent or selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein the aryl, heteroaryl, or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, and amino, wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 substituents independently selected from hydrido, alkyl, and aralkyl.
More generally, a contemplated compound includes an inhibitor utilized as discussed above, as well as a pro-drug form of such a compound and also an intermediate used in the synthesis of a hydroxamate or hydroxamate pro-drug. Such a more general compound corresponds in structure to formula II: 
Here, R1, R2, R3a and R3b are as before described.
R20 is (a) xe2x80x94Oxe2x80x94R21, wherein R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, and a pharmaceutically acceptable cation, (b) xe2x80x94NHxe2x80x94Oxe2x80x94R22, wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ) carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide systhesis resin and the like, wherein trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl, or (c) xe2x80x94NHxe2x80x94Oxe2x80x94R14, where R14 is hydrido, a pharmaceutically acceptable cation, or C(W)R15 wherein W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or (iii) wherein the amino C1-C6-alkyl nitrogen and 2 substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
More particularly, a benefit of this invention is the provision of a compound and composition effective for selectively inhibiting certain metalloproteinases, such as 1 or both of MMP-2 and MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer""s Disease, coronary thrombosis and bone disease.
An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.
A still further benefit of the invention is that a contemplated compound exhibits greater inhibition of MMP-2 than MMP-13.
A still further advantage of the invention is that a contemplated compound exhibits inhibitory activity against the adamalysin family of enzymes.
Yet another advantage of the invention is the provision of a process for preparing such compounds.
Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
A further advantage of the invention is the provision of a process for preparing such compositions.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
In accordance with the present invention, it has been discovered that certain sulfamato hydroxamic acids (hydroxamates) are effective for inhibition of matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain sulfamato hydroxamates are effective for inhibition of 1 or both of MMP-2 and MMP-13, which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity. Included in that pathological activity is the assistance of tumors and tumor cells in the process of penetrating basement membrane, and developing a new or improved blood supply, i.e., angiogenesis.
Moreover, it has been discovered that these sulfamato hydroxamates are selective in the inhibition of 1 or both of MMP-2 and MMP-13 without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that a contemplated sulfamato hydroxamate of the invention, or a pharmaceutically acceptable salt thereof, is particularly active in inhibiting of 1 or both of MMP-2 and MMP-13 in an in vitro assay that is predictive of in vivo activity. In addition, while being selective for 1 or both of MMP-2 and MMP-13, a contemplated sulfamato hydroxamate, or its salt, has a limited or minimal in vitro inhibitory effect on MMP-1. This point is illustrated in the Inhibition Table hereinafter. Put differently, a contemplated compound can inhibit the activity of MMP-2 or MMP-13 compared to MMP-1.
The advantages of the selectivity of a contemplated compound can be appreciated, without wishing to be bound by theory, by considering the therapeutic uses the compounds. For example, inhibition of MMP-1 is suggested to be undesirable due to its role as a housekeeping enzyme, helping to maintain normal connective tissue turnover and repair. Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 has been suggested to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 compared with inhibition MMP-1 is highly desirable because a MMP-13 inhibitor can have a positive effect on disease progression in a patient in addition to having an anti-inflammatory effect.
Inhibition of MMP-2 can be desirable for inhibition of tumor growth, metastasis, invasion and/or angiogenesis. A profile of selective inhibition of MMP-2 relative to MMP-1 can provide a therapeutic advantage. A contemplated compound not only is substantially more active in inhibiting MMP-2 than MMP-1, a contemplated compound also exhibits greater inhibition of MMP-2 than MMP-13.
A further advantage to MMP inhibitors with selective inhibition profiles is their suitability for use in combination with other types of medicaments. For example, a patient can be treated with an MMP inhibitor compound for the inhibition of angiogenesis in combination with a second, third or fourth drug of the traditional anti-tumor type, such as taxol, cis-platinum or doxorubicin. A further advantage is that the administration of a MMP inhibitor with a selective inhibition profile can permit the reduction in dosage of the drugs being administered to the patient. This is an especially important advantage given both the toxicities and dosing limits of traditional anti-tumor drugs.
A contemplated selective MMP inhibitor compound useful in a contemplated process can be administered to by various routes and provide adequate therapeutic blood levels of enzymatically active inhibitor. A compound can be administered, for example, by the oral (IG, PO) or intravenous (IV) routes. Oral administration is advantageous if the patient is ambulatory, not hospitalized, physically able and sufficiently responsible to take drug at the required intervals. This is true even if the person is being treated with more than 1 drug for 1 or more diseases. On the other hand, IV drug administration is an advantage in a hospital setting wherein the dose and thus the blood levels can well controlled. A contemplated inhibitor can also be formulated for IM administration if desired, This route of administration can be desirable for the administration of prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.
Thus, in one embodiment, the present invention is directed to a treatment process that comprises administering a contemplated sulfamato hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having a condition associated with pathological matrix metalloprotease activity. A contemplated sulfamato hydroxamate inhibitor compound useful in such a process inhibits the activity of 1 or both of MMP-2 and MMP-13, and exhibits substantially less inhibitory activity against at least MMP-1 in the in vitro assay noted above and discussed in detail hereinafter. A sulfamato hydroxamate inhibitor compound for use in a contemplated process corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof: 
Here, R1 and R2 are preferably taken together with the carbon to which they are bonded form a cycloalkyl or more preferably a heterocyclo group either of which is optionally substituted by 1, 2, or 3 Rx substituents, or R1 and R2 are independently selected from the group consisting of:
hydrido,
an alkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkyloxyalkyl group, optionally substituted with 1, 2, or 3 subtitiuents independently selected from Rx substituents,
an alkylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an alkynyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an aryl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an aryloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkyl or bicycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkylalkyl or bicycloalkylalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkyloxyalkyl or bicycloalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkylalkyloxyalkyl or bicycloalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a cycloalkylthioalkyl or bicycloalkylthioalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx,
cycloalkylalkylthioalkyl or bicycloalkylalkylthioalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a heterocyclo group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a heterocycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents
a heteroaryl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a biarylalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
an arylalkynyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents,
a heterocycloalkylthio group, optionally substituted with 1, 2, or 3 substituents selected independently from Rx substituents,
a heterocycloalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents selected independently from Rx substituents,
a heteroarylalkenyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents, and
a heteroarylalkyloxyalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from Rx substituents.
Rx is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, RcRd-amino (xe2x80x94NRcRd), RcRd-aminoalkyl, nitro, nitroso, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, alkoxyalkyl, Rc-oxyalkyl, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, alkyloxycarbonyl-Rc-amino, arylalkyloxycarbonyl-Rc-amino, aryloxycarbonyloxy, carboxy, RcRd-aminocarbonyloxy, RcRd-aminocarbonyl, RcRd-aminoalkanoyl, hydroxy-Rc-aminocarbonyl, RcRd-aminosulfonyl, arylsulfonyl(Rc)amino, RcRd-aminoalkoxy, RcRd-aminocarbonyl(Rc)amino, trifluoromethylsulfonyl(Rc)amino, heteroarylsulfonyl-(Rc)amino, alkylsulfonyl, arylsulfonyl(Rc)amino, arylsulfonyl(Rc)aminocarbonyl, alkylsulfonyl-(Rc)amino, arylcarbonyl(Rc)-aninosulfonyl, and alkylsulfonyl(Rc)aminocarbonyl.
Rc and Rd are independently selected from the group consisting of hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, and aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with 1 or 2 Ry radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with 1, 2, or 3 substituents independently selected from Rw substituents or a heteroaryl group optionally substituted with 1, 2, or 3 substituents independently selected from Rv substituents.
Ry is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and hydroxyalkyl, each of which groups is optionally substituted by 1 or 2 substituents independently selected from Ru substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl.
Rv is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RyRz-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RyRz-aminocarbonyloxy, RyRz-aminocarbonyl, RyRz-aminoalkanoyl, hydroxyaminocarbonyl, RyRz-aminosulfonyl, RyRz-aminocarbonyl(Ry)amino, trifluoromethylsulfonyl(Ry)amino, heteroarylsulfonyl-(Ry)amino, arylsulfonyl(Ry)amino, arylsulfonyl(Ry)-aminocarbonyl, alkylsulfonyl(Ry)amino, arylcarbonyl-(Ry)aminosulfonyl, and alkylsulfonyl(Ry)-aminocarbonyl.
Rw is selected from the group consisting of hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehydo (CHO, formyl), hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RyRz-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RyRz-aminocarbonyloxy, RyRz-aminocarbonyl, RyRz-aminoalkanoyl, hydroxyaminocarbonyl, RyRz-aminosulfonyl, RyRz-aminocarbonyl(Ry)amino, trifluoromethylsulfonyl(Ry)amino, heteroarylsulfonyl-(Ry)amino, arylsulfonyl(Ry)amino, arylsulfonyl(Ry)-aminocarbonyl, alkylsulfonyl(Ry)amino, arylcarbonyl-(Ry)aminosulfonyl, and alkylsulfonyl(Ry)-aminocarbonyl.
Rz is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and hydroxyalkyl, each of which groups are optionally substituted by 1 or 2 Ru substituents.
Ru is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and hydroxyalkyl, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group.
As to R3a and R3b.
R3a and R3b are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, heterocyclo, heteroaryl, cycloalkyl, and alkoxyalkyl, each of which groups is optionally substituted by an xe2x80x94AREY substituent, wherein
A is:
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94Sxe2x80x94,
(3) xe2x80x94N(Re)xe2x80x94,
(4) xe2x80x94COxe2x80x94N(Re) or xe2x80x94N(Re)xe2x80x94COxe2x80x94,
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94,
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94,
(7) xe2x80x94HCxe2x95x90CHxe2x80x94,
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94,
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94,
(10) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94,
(11) xe2x80x94Nxe2x95x90Nxe2x80x94,
(12) xe2x80x94NHxe2x80x94NHxe2x80x94,
(13) xe2x80x94CSxe2x80x94N(Re)xe2x80x94 or xe2x80x94N(Re)xe2x80x94CSxe2x80x94,
(14) xe2x80x94CH2xe2x80x94,
(15) xe2x80x94Oxe2x80x94[(CH2)1-8]xe2x80x94 or xe2x80x94[(CH2)1-8]Oxe2x80x94,
(16) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94, or
(17) absent and R is directly connected to R3a or R3b, or both R3a and R3b;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl-oxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with 1 or 2 radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
E is:
(1) xe2x80x94CO(Rw)xe2x80x94 or xe2x80x94(Rw)COxe2x80x94,
(2) xe2x80x94CON(Re)xe2x80x94 or xe2x80x94(Re)NCOxe2x80x94,
(3) xe2x80x94COxe2x80x94,
(4) xe2x80x94SO2xe2x80x94Rw or xe2x80x94RwSO2xe2x80x94,
(5) xe2x80x94SO2xe2x80x94,
(6) xe2x80x94N(Re)xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94N(Re)xe2x80x94, or
(7) absent and R is bonded directly to Y;
Y is absent or is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Rcoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 substituents independently selected from hydrido, alkyl, and aralkyl; and
Re is selected from hydrido, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl, and Rc, Rd and Rw are as defined before; or
R3a and R3b taken together with the nitrogen atom to which they are bonded form a group xe2x80x94GAREY (R3) wherein:
G is N-heterocyclo;
A is:
(1) xe2x80x94Oxe2x80x94,
(2) xe2x80x94Sxe2x80x94,
(3) xe2x80x94NRexe2x80x94,
(4) xe2x80x94COxe2x80x94N(Re) or xe2x80x94N(Re)xe2x80x94COxe2x80x94,
(5) xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94,
(6) xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94,
(7) xe2x80x94HCxe2x95x90CHxe2x80x94,
(8) xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94,
(9) xe2x80x94Cxe2x89xa1Cxe2x80x94,
(10) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94,
(11) xe2x80x94Nxe2x95x90Nxe2x80x94,
(12) xe2x80x94NHxe2x80x94NHxe2x80x94,
(13) xe2x80x94CSxe2x80x94N(Re)xe2x80x94 or xe2x80x94N(Re)xe2x80x94CSxe2x80x94,
(14) xe2x80x94CH2xe2x80x94,
(15) xe2x80x94Oxe2x80x94[(CH2)1-8]xe2x80x94 or xe2x80x94[(CH2)1-8]Oxe2x80x94,
(16) xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94, or
(17) absent and R is directly connected to G;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl-oxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with 1 or 2 radicals selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxyearbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
E is:
(1) xe2x80x94CO(Rw)xe2x80x94 or xe2x80x94(Rw)COxe2x80x94,
(2) xe2x80x94CONHxe2x80x94 or xe2x80x94HNCOxe2x80x94,
(3) xe2x80x94COxe2x80x94,
(4) xe2x80x94SO2xe2x80x94Rwxe2x80x94 or xe2x80x94Rwxe2x80x94SO2xe2x80x94,
(5) xe2x80x94SO2xe2x80x94,
(6) xe2x80x94NHxe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94NHxe2x80x94, or
(7) absent and R is bonded directly to Y; and
Y is absent or selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein the aryl, heteroaryl, or heterocycloalkyl is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, and amino, wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 substituents independently selected from hydrido, alkyl, and aralkyl.
More generally, a contemplated compound includes an inhibitor utilized as discussed above, as well as a pro-drug form of such a compound and also an intermediate used in the synthesis of a hydroxamate or hydroxamate pro-drug. Such a more general compound corresponds in structure to formula II, below: 
Here, R1, R2, R3a and R3b are as before described with the above preferences.
R20 is (a) xe2x80x94Oxe2x80x94R21, wherein R21 is selected from the group consisting of hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, and a pharmaceutically acceptable cation, (b) xe2x80x94NHxe2x80x94Oxe2x80x94R22, wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ) carbonyl-C1-C6-alkoxy, trisubstituted silyl, o-nitrophenyl, peptide systhesis resin, or the like, wherein the trisubstituted silyl is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl, or (c) xe2x80x94NHxe2x80x94Oxe2x80x94R14, wherein R14 is hydrido, a pharmaceutically acceptable cation, or C(W)R15 wherein W is O or S and R15 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and 2 substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
The substituent xe2x80x94NR3aR3b can also be referred to as a R3 group. One exemplary R3 group is xe2x80x94N(CH3)2, whereas another is the before-discussed substituent group xe2x80x94GAREY that is present in more preferred compounds as is discussed hereinbelow.
One group of more preferred compounds correspond ion structure to formula III, formula IIIA or a pharmaceutically acceptable salt thereof: 
wherein R1, R2, R20, and xe2x80x94GAREY are as discussed before, with the before-described preferences.
Yet another more preferred group of contemplated compounds correspond ion structure to formula IV, formula IVA or a pharmaceutically acceptable salt thereof: 
wherein substituents R1, R2, R20, and xe2x80x94AREY are as discussed before, with the before-described preferences.
A still more preferred group of contemplated compounds correspond ion structure to formula V, formula VA or a pharmaceutically acceptable salt thereof: 
wherein substituents R20 and xe2x80x94AREY are as discussed before, with the before-described preferences.
Another more preferred group of contemplated compounds correspond ion structure to formula VI, formula VIA or a pharmaceutically acceptable salt thereof: 
wherein substituents R1, R2, R20 and xe2x80x94EY are as discussed before, with the before-described preferences, and A is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Sxe2x80x94.
A still more preferred group of contemplated compounds correspond ion structure to formula VII, formula VIIA or a pharmaceutically acceptable salt thereof: 
wherein substituents R20 and xe2x80x94EY are as discussed before as part of an xe2x80x94AREY or xe2x80x94GAREY group, with the before-described preferences, and A is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Sxe2x80x94.
Another group of preferred compounds for use in a contemplated process has a structure that corresponds to formulas VIII and VIIIA, below, or a pharmaceutically acceptable salt thereof: 
Here, R3a, R3b and R20 are as defined before, with the before-described preferences; m is zero, 1 or 2; n is zero, 1 or 2; p is zero, 1 or 2; and the sum of m+n+p=1, 2, 3, or 4.
As to X, Y, and Z:
(a) one of X, Y, and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining 2 of X, Y, and Z are CR8R9, and CR10R11, or
(b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y, and Z being CR8R9, or
(c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of: 
xe2x80x83wherein wavy lines are bonds to the atoms of the depicted ring.
R6 and R6xe2x80x2 are independently selected from the group consisting of hydrido, C1-C6-alkanoyl, C6-aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, C6-aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, C6-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C6-arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyliminocarbonyl, C6-aryliminocarbonyl, C5-C6-heterocycloiminocarbonyl, C6-arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, C6-arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9xe2x80x94C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, an aminocarbonyl wherein the aminocarbonyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, C3-C8-cycloalkyl and a C1-C6-alkanoyl group, hydroxyaminocarbonyl, an aminosulfonyl group wherein the aminosulfonyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, C3-C8-cycloalkyl and a C1-C6-alkanoyl group, an amino-C1-C6-alkylsulfonyl group wherein the amino-C1-C6-alkylsulfonyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, C3-C8-cycloalkyl and a C1-C6-alkanoyl group and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, C3-C8-cycloalkyl and a C1-C6-alkanoyl group.
R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group.
R8 and R9 and R10 and R11 are independently selected from the group consisting of hydrido, hydroxy, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and amino-C1-C6-alkyl, wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only 1 of R8 and R9 or R10 and R11 is hydroxy.
R12 and R12xe2x80x2 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with 1 or 2 radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl.
R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group.
A compound of formulas VIII and VIIIA thus includes a compound illustrated by formulas V, VA, VII and VIIA discussed above, as well as other compounds of formulas I and II.
A group of particularly preferred compounds of formula VIII and VIIIA correspond in structure to formula IX or IX, below, or a pharmaceutically acceptable salt thereof: 
wherein R6, R20, and xe2x80x94AREY are as described before, with the before-described preferences.
A still more preferred group of contemplated compounds correspond in structure to formula X, formula XA or a pharmaceutically acceptable salt thereof: 
wherein R6, R20, and xe2x80x94EY are as discussed before as part of an xe2x80x94AREY or xe2x80x94GAREY group, with the before-described preferences, and wherein A is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Sxe2x80x94.
A group of contemplated compounds that is even still more preferred contain a xe2x80x94NR3aR3b group in which R3a and R3b taken together with the nitrogen atom to which they are bonded form a group xe2x80x94GAREY where G is a disubstituted piperazinyl group correspond in structure to formula XI, formula XIA or a pharmaceutically acceptable salt thereof: 
wherein the definitions for X, Y, Z, m, n, p, A, E, Y, and R20 are as before discussed, with the before-described preferences and A being absent.
Without wishing to be bound by theory, it is believed that when substituent A is absent so that R is bonded directly to G, the bond flexibility provided by the non-sulfamido nitrogen of the piperazinyl group, xe2x80x94Gxe2x80x94, to the remainder of the xe2x80x94AREY substituent present provides enhanced fit of an inhibitor into the binding pocket of gelatinase and MMP-13 enzymes, while not appreciably altering the binding to MMP-1. It is also believed that similar flexibility and enhanced binding to these enzymes is achieved where xe2x80x94SO2Gxe2x80x94 is a substituted N-sulfonamidopiperidinyl group and substituent A is a single atom such as xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94 or xe2x80x94NHxe2x80x94.
Of the compounds of formulas XI and XIA, a compound corresponding in formula to formulas XII or XII, formulas XIIA or XIIIA or a pharmaceutically acceptable salt thereof is yet more preferred: 
wherein R6, R20, and xe2x80x94EY are as described before, with the before-described preferences.
It is particularly preferred that both substituents A and E be absent in a compound of formulas XII, XIII, XIIA and XIIIA so that the substituted phenyl ring, substituent or moiety R, is bonded on 1 side directly to 1 nitrogen atom of the piperazinyl ring, and on the other side, that phenyl ring is bonded directly to the Y group.
The structures of several particularly preferred compounds of the above formulas are shown below along with the Example in which the particular compound is synthesized: 
Further particularly preferred compounds include:
4-[(hydroxyamino)-carbonyl]-4-[[4-[4-(trifluoromethyl)-phenoxy]-1-piperidinyl]sulfonyl]-1-piperidinecarboxylate;
N-hydroxy-2-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]-sufonyl]acetanmide;
N-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-acetamide;
N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethyl)-phenoxy]-1-piperidinyl)sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(2-Methoxyethyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide;
tetrahydro-N-hydroxy-4-[[4-(4-nitrophenoxy)-1-piperidinyl]sulfonyl]-2H-pyran-4-carboxamide;
N-hydroxy-1-(phenylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(phenylmethyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]-sulfonyl]-4-piperidinecarboxylate;
N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(2-methoxyethyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxylate;
N-hydroxy-2-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]acetamide;
N-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-acetamide;
tetrahydro-N-hydroxy-4-[[4-[4-(trifluoromethoxy)-phenoxy]-1-piperidinyl]sulfonyl]-2H-pyran-4-carboxamide;
tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-2H-pyran-4-carboxamide;
N-hydroxy-1-(phenylnethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(phenylmethyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide;
N-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(2-pyridinylmethyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]-sulfonyl]-4-piperidinecarboxamide;
N-hydroxy-1-(2-pyrimidinyl)-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(2-pyrimidinyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]-sulfonyl]-4-piperidinecarboxamide;
N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-piperidinecarboxamide, monohydrochloride;
N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-piperidinecarboxamide;
1-(5-ethyl-2-pyrimidinyl)-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(5-ethyl-2-pyrimidinyl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide;
tetrahydro-N-hydroxy-4-[[4-[4-(trifuoromethoxy)-phenoxy]-1-piperidinyl]sulfonyl]-2H-thiopyran-4-carboxamide;
tetrahydro-N-hydroxy-4-[[4-[4-(trifluoromethoxy)-phenoxy]-1-piperidinyl]sulfonyl]-2H-thiopyran-4-carboxamide, 1,1-dioxide;
tetrahydro-N-hydroxy-4-[[4-[4-(trifluoromethyl)-phenoxy]-1-piperidinyl]sulfonyl]-2H-thiopyran-4-carboxamide;
N-hydroxy-4[[1xe2x80x2-(n-pentyl)[4,4xe2x80x2-bipiperidin]-1-yl]sulfonyl]-tetrahydro-2H-pyran-4-carboxamide;
N-hydroxy-4[[1xe2x80x2-(4-methoxybenzoyl)[4,4xe2x80x2-bipiperidin]-1-yl]sulfonyl]-tetrahydro-2H-pyran-4-carboxamide;
N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(2-furanylmethyl)-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide;
4-[[4-[4-[4-(trifluoromethyl)phenoxy]phenoxy]-1-piperidinyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;
tetrahydro-N-hydroxy-4-[[4-(4-pentylphenyl)-1-piperazinyl]sulfonyl]-2H-pyran-4-carboxamide, monohydrochloride;
tetrahydro-N-hydroxy-4-[(4-phenyl-1-piperazinyl)-sulfonyl]-2H-pyran-4-carboxamide;
N-hydroxy-1-(2-methoxyethyl)-4-[[4-[[4-(trifluoromethyl)benzoyl]amino]-1-piperidinyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
N-hydroxy-1-phenyl-4-[[4-[4-(trifluoromethoxy)-phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
N-hydroxy-1-phenyl-4-[[4-[4-(trifluoromethyl)-phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
4-[[4-[4-(1,1-dimethylethyl)phenyl]-1-piperazinyl]-sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrochloride;
4-[[4-(4-butoxyphenyl)-1-piperazinyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, dihydrochloride;
tetrahydro-N-hydroxy-4-[[4-[[4-[(trifluoromethyl)-thio]phenyl]-thio]-1-piperidinyl]sulfonyl]-2H-pyran-4-carboxamide;
4-[[4-(4-bromophenyl)-4-fluoro-1-piperidinyl]-sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;
4-[[4-[4-(3,5-dimethylphenoxy)phenoxy]-1-piperidinyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;
1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
N-hydroxy-1-(iminophenylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
N-hydroxy-1-[(4-hydroxyphenyl)iminomethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-(2-furanylcarbonyl)-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide;
N-hydroxy-1-[2-(methylthio)-4-pyrimidinyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyi]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
1-cyclopropyl-N-hydroxy-4-[[4-[4-(tri-fluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-pipenrdinecarboxamide, monohydrochloride;
N-hydroxy-4-[[1xe2x80x2-(2-methoxyphenyl)[4,4xe2x80x2-bipiperidin]-1-yl]sulfonyl]-1-(phenylmethyl)-4-piperidinecarboxamide, dihydrochloride;
4-(1,4-dioxa-8-azaspiro-[4.5]dec-8-ylsulfonyl)-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;
4-[[4-[[(3R,5R)-rel-3,5-dimethyl-1-piperidinyl]-carbonyl]-1-piperidinyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;
4-[[4-[[(3R,5S)-rel-3,5-dimethyl-1-piperidinyl]-carbonyl]-1-piperidinyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;
N-hydroxy-1-(4-methylphenyl)-4-[[4-[4-(trifluoro-methyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
N-hydroxy-1-(4-methylphenyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]-1-piperidinyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride;
tetrahydro-N-hydroxy-4-[[4-(phenylmethyl)-1-piperazinyl]-sulfonyl]-2H-pyran-4-carboxamide, monohydrochloride;
N-hydroxy-1-(phenylmethyl)-4-[(4-phenyl-1-piperazinyl)sulfonyl]-4-piperidinecarboxamide, bis(trifluoroacetate);
N-hydroxy-1-(phenylmethyl)-4-[(4-phenyl-1-piperazinyl)sulfonyl]-4-piperidinecarboxamide, dihydrochloride; and
4-[[4-(4-butoxy-3-methylphenyl)-1-piperazinyl]-sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide.
Most preferred are compounds or their salts are those of Examples 19, 51, 47, 17, 42, 15, 12, 14, 35, 32, 23, 3, 2, 36, 43, 44, 13, 6, 46, 28, 30, 10, 50, 9, 18, 31, 16, 8, 55, 11, 38, 53, 33, 41, 40, 4, 54, 34, and 5.
Table 1 through Table 221, below, illustrate several compounds useful in a process of this invention. Each group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The generic symbols, e.g., R1, R2 and the like, are as shown in the tables and are not necessarily as defined before. This system is well known in the chemical communication arts, and is widely used in scientific papers and presentations. For example in Table 1, the R1 and R2 groups of the generic structure shown and of formula I are illustrated as being taken together with the carbon to which they are bonded illustrate structural variables that can substitute for the R1 and R2 groups shown in the balance of the table. There are 12 R1 and R2 groups shown that are used to represent, in a non-limiting manner, 12 distinct compounds that can be prepared for use in the invention.
Also according to the present invention, there are provided processes for preparing the compounds of the present invention. Synthesis schemes, generic Schemes 1-4 and specific Schemes A-D, illustrating such processes are illustrated below. 
P is a protecting group
Pxe2x80x2 is a protecting group
L is a leaving group
R1, R2, R3a, R3b are as defined herein 
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 18 carbon atoms, preferably 1 to about 12 carbon atoms, and more preferably 1 to about 8 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 18 carbon atoms preferably 2 to about 12 carbon atoms, and more preferably, 2 to about 8 carbon atoms. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.
The term xe2x80x9calkynylxe2x80x9d, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 18 carbon atoms, preferably 2 to about 12 carbon atoms, and more preferably, 2 to about 8 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9ccarbonylxe2x80x9d or xe2x80x9coxoxe2x80x9d, alone or in combination, means a xe2x80x94C(xe2x95x90O)xe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted. The term carbonyl is also intended to encompass a hydrated carbonyl group xe2x80x94C(OH)2xe2x80x94.
The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d, alone or in combination, means a xe2x80x94SH group. The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, means an amine or xe2x80x94NH2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine xe2x80x94N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a xe2x80x94N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
Amines, amino groups and amides are compounds that can be designated as primary (Ixc2x0), secondary (Ixc2x0) or tertiary (IIIxc2x0) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IVxc2x0) means a nitrogen with four substituents [xe2x80x94N+(substituent)4] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [xe2x80x94N+(substituent)3xe2x80x94Oxe2x88x92]; i.e., the charges are internally compensated.
The term xe2x80x9ccyanoxe2x80x9d, alone or in combination, means a xe2x80x94C-triple bond-N (xe2x80x94Cxe2x89xa1N, ntrile) group. The term xe2x80x9cazidoxe2x80x9d, alone or in combination, means a xe2x80x94N-triple bond-N (xe2x80x94Nxe2x89xa1N) group. The term xe2x80x9chydroxylxe2x80x9d, alone or in combination, means a xe2x80x94OH group. The term xe2x80x9cnitroxe2x80x9d, alone or in combination, means a xe2x80x94NO2 group. The term xe2x80x9cazoxe2x80x9d, alone or in combination, means a xe2x80x94Nxe2x95x90Nxe2x80x94 group wherein the bonds at the terminal positions can be independently substituted.
The term xe2x80x9chydrazinoxe2x80x9d, alone or in combination, means a xe2x80x94NHxe2x80x94NHxe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
The term xe2x80x9csulfonylxe2x80x9d, alone or in combination, means a xe2x80x94SO2xe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfoxidoxe2x80x9d, alone or in combination, means a xe2x80x94SOxe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted.
The term xe2x80x9csulfonexe2x80x9d, alone or in combination, means a xe2x80x94SO2xe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfenamidexe2x80x9d, alone or in combination, means a xe2x80x94SONxe2x95x90 group wherein the remaining three depicted bonds (valences) can be independently substituted. The term xe2x80x9csulfidexe2x80x9d, alone or in combination, means a xe2x80x94Sxe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical or redicals with one, two or three oxygen atoms wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, methoxyethoxypropyl (CH3OCH2CH2OCH2CH2CH2xe2x80x94), 1,1-dimethoxyethane. 1,2-dimethoxyethane and the like. The term xe2x80x9calkyloxyxe2x80x9d is used to mean a substituted alkoxy group.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term xe2x80x9ccycloalkylalkylxe2x80x9d means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
A heterocyclic (heterocyclo) group or the like alone or in combination is a saturated, unsaturated or partially unsaturated (non-aromatic) monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms, typically one to three hetero atoms selected from nitrogen, oxygen and sulfur. A heterocyclic group can contain 4 to about 14 atoms in the one to three rings that also contain at least one nitrogen, oxygen or sulfur atom in addition to the carbon atoms. Preferably, a single ring is present and that ring contains 5 to 7 atoms and one hetero atom. Sulfur atoms, independently, may optionally be oxidized to, for example, xe2x80x94SOxe2x80x94 or xe2x80x94SO2-groups. Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, alkyl, alkoxy, oxo, and the like or as stated herein, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or other groups listed herein or on a tertiary nitrogen atom (i.e., xe2x95x90Nxe2x80x94) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide [xe2x95x90N(O)xe2x80x94] group. A xe2x80x9cheterocycloalkylxe2x80x9d group is an alkyl group substituted with a heterocyclo group.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.
The term xe2x80x9cbiarylxe2x80x9d, alone or in combination means an aryl ring as define herein connected directly by a single bond to further aryl rings. Exemplary biaryl radicals include phenyl-phenyl (biphenyl), 2-phenylnapthlenyl and phenylindenyl and 1-phenyl-anthracenyl radicals.
The term xe2x80x9cheteroarylxe2x80x9d alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen. Sulfur atoms, independently, may optionally be oxidized to, for example, xe2x80x94SOxe2x80x94 or xe2x80x94SO2-groups. Nitrogen atoms, independently, may be optionally oxidzed to, for example, N-oxide groups or quaternized. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyridyl-N-oxide, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, thienyl-S-oxide, triazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, xcex2-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals.
The termxe2x80x9cheterocyclocarbonylxe2x80x9d, alone or in combination, means a heterocyclogroup attached to a xe2x80x94Cxe2x95x90O)-group.
The term xe2x80x9cheterocyclooxycarbonyxe2x80x9d, alone or in combination, means a heterocyclogroup attached to a xe2x80x94O(Cxe2x95x90O)-group.
The term xe2x80x9cheterocycloalkoxycarbonyxe2x80x9d, alone or in combination, means a heterocyclogroup attached to a -alkylO(Cxe2x95x90O)-group.
The termxe2x80x9cheterocycloalkylxe2x80x9d, alone or in combination, means a heterocyclogroup attached to an alkyl group.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.
The term xe2x80x9caralkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the formula aralkyl-Oxe2x80x94C(O)xe2x80x94 in which the term xe2x80x9caralkylxe2x80x9d has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
The term xe2x80x9caryloxyxe2x80x9d means a radical of the formula aryl-Oxe2x80x94 in which the term aryl has the significance given above. The phenoxy radical is an exemplary aryloxy radical.
The terms xe2x80x9cheteroaralkylxe2x80x9d and xe2x80x9cheteroaryloxyxe2x80x9d mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals. Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.
The terms xe2x80x9calkanoylxe2x80x9d or xe2x80x9calkylcarbonylxe2x80x9d, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
The term xe2x80x9ccycloalkylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.
The terms xe2x80x9caralkanoylxe2x80x9d or xe2x80x9caralkylcarbonylxe2x80x9d mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.
The terms xe2x80x9caroylxe2x80x9d or xe2x80x9carylcarbonylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
The term xe2x80x9ccycloalkylalkoxycarbonylxe2x80x9d means an acyl group of the formula cycloalkylalkyl-Oxe2x80x94COxe2x80x94 wherein cycloalkylalkyl has the significance given above. The term xe2x80x9caryloxyalkanoylxe2x80x9d means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclooxycarbonylxe2x80x9d means an acyl group having the formula heterocyclo-Oxe2x80x94COxe2x80x94 wherein heterocyclo is as defined above.
The term xe2x80x9cheterocycloalkanoylxe2x80x9d is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term xe2x80x9cheterocycloalkoxycarbonylxe2x80x9d means an acyl radical of the formula heterocyclo-substituted alkane-Oxe2x80x94COxe2x80x94 wherein heterocyclo has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical represented by the formula heteroaryl-Oxe2x80x94COxe2x80x94 wherein heteroaryl has the significance given above.
The term xe2x80x9caminocarbonylxe2x80x9d (carboxamide) alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (xe2x80x94NH2) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited. A hydroxamate is a N-hydroxycarboxamide.
The term xe2x80x9caminoalkanoylxe2x80x9d means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
The term xe2x80x9chalogenxe2x80x9d means fluoride, chloride, bromide or iodide. The term xe2x80x9chaloalkylxe2x80x9d means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
The term xe2x80x9cperfluoroalkylxe2x80x9d means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
The term xe2x80x9cperfluoroalkoxyxe2x80x9d alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F3Cxe2x80x94Oxe2x80x94), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.
The term xe2x80x9cperfluoroalkylthioxe2x80x9d alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkylthio groups, in addition to trifluoromethylthio (F3Cxe2x80x94Sxe2x80x94), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.
The term xe2x80x9caromatic ringxe2x80x9d in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before.
Compounds contemplated herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or nonracemic mixtures. A compound can also exist in other isomeric forms such as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomeric isomers, alpha and beta isomers, axial and equatorial isomers and isomers due to hindered rotation. An isomer can exist in equilibrium with another isomer in a mammal or a test system. Such isomeric equiliberia can also occur during synthesis, storage, formulation, as formulated pharmaceuticals, as liquids, solutions, solids, polymorphs and the like. Such a compound can also exist as an isomeric equilibrium system with a solvent or water, for example, as a hydrated ketone or aldehyde, hemiketal, hemiacetal, ketal, acetal or other class or type of solvate as is well known in the art. All isomers are included as compounds of this invention.
The chemical reactions described herein are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, are applicable to the preparation of the corresponding compounds that are contemplated.
xe2x80x9cMxe2x80x9d utilized in the reaction schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.
It is understood that the definition of the compounds of the various formulas herein that contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof that posses the activity discussed herein. In particular, it encompasses racemic modifications and any optical isomers which possesses the indicated activity. Optical isomers can be obtained in pure form by standard separation techniques.
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound described hereinbefore in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of administration repeated a plurality of times is particularly contemplated.
A contemplated compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
Also contemplated is the similar use of a contemplated compound in the treatment of a disease state that can be affected by the activity of metalloproteases such as TNF-xcex1 convertase or a member of the adamalysin family of enzymes such as ADAM 10. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used, where appropriate, in the form of a pharmaceutically acceptable amine salt derived from an inorganic or organic acid. Exemplary acid salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane-propionate, dodecylsulfate, ethanesulfonate, formate, glutamate, glucoheptanoate, gluconate, glucurantae, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isocitrate, lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, oxalacetate, palnoate, pectinate, persulfate, 3-phenylpropionate, phosphate, monohydrogen phosphate, dihydrogen phosphate, picrate, pivalate, propionate, pyruvate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl (C1-C6) halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C8-C20) halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromides and iodides, aralkyl halides like benzyl and phemethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
Other compounds useful in this invention that are acids can also form pharmaceutically acceptable salts. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminun, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,Nxe2x80x2-dibenzyl-ethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
Total daily dose administered to a host mammal in single or divided doses of an MMP enzyme-inhibiting effective amount can be in amounts, for example, of about 0.001 to about 100 mg/kg body weight daily, preferably about 0.001 to about 30 mg/kg body weight daily and more usually about 0.01 to about 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose.
A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should such dosing be desired by the person prescribing the drug. Such composition can be administered 1 to 6 times a day, more usually 1 to 4 times a day.
The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
A compound useful in the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, which is preferred, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington""s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, staRch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.
Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations and their meanings are as follows:
BOC=t-butoxycarbonyl
DEAD=diethyl azodicarboxylate.
DMF=dimethylformamide.
DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
EtOAc=ethyl acetate
EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride
Et2O=diethyl ether
HOBT=1-hydroxybenzotriazole
MeOH=methanol
MeCl2=methylene chloride
MsCl=methanesulfonyl chloride
NMM=N-methyl morpholine. THF=tetrahydroftuan
TsCl=toluenesulfonyl chloride
THP-O-hydroxylamine=O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine